Benzomorphan analogs and the use thereof

Abstract

The present invention is directed to Benzomorphan Analog compounds of the Formula I″, Formula IA″, Formula IB″, Formula IC″, or Formula ID″ as shown below; and related Formula I′, Formula IA′, Formula IB′, Formula IC′, or Formula ID′; Formula I, Formula IA, Formula IB, Formula IC, or Formula ID; wherein R 1 , R 2a , R 2b , R 3 and R 4 are as defined herein. Compounds of the Invention are useful for treating pain, constipation, and other conditions modulated by activity of opioid and ORL-1 receptors.

What is claimed is: 
     
       1. A compound of Formula I′: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of —(C 1 -C 10 )alkyl, (C 3 -C 12 )cycloalkyl-(C 1 -C 6 )alkyl-, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, diphenyl(C 1 -C 6 )alkyl-, each of which is optionally substituted by 1, 2 or 3 independently selected R 9  groups; 
         R 2a  is absent, H or OH; 
         R 2b  is —Z-G-R 10 ; 
         Z is absent; 
         G is selected from the group consisting of:
 ═CH, NR 8 , ═N—O, and ═N—NH; provided that when R 2a  is absent, G is not NR 8 ; 
 
         R 10  is selected from the group consisting of —(C 1 -C 10 )alkyl, —(C 2 -C 12 )alkenyl, —C(═O), —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 2 -C 6 )alkenyl, —C(═O)-(6- to 14-membered)aryl, —C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —(C 2 -C 12 )alkynyl, —(C 1 -C 10 )alkoxy, —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, CN, NR 5 R 6 , —(C 1 -C 6 )alkyl-NR 5 R 6 , —CONR 5 R 6 , —(C 1 -C 6 )alkyl-CO—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , —CO—(CH 2 ) n —COOR 7 , —CO—(CH 2 ) n —CO—NR 5 R 6 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, —(C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 6 -C 14 )bicycloalkyl, ((C 6 -C 14 )bicycloalkyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkyl, ((C 8 -C 20 )tricycloalkyl)-(C 1 -C 6 )alkyl-, —(C 7 -C 14 )bicycloalkenyl, ((C 7 -C 14 )bicycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkenyl, ((C 8 -C 20 )tricycloalkenyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-, phenyl, benzyl and naphthyl; each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of —OH, (═O), halo, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl-, dihydroxy(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkoxy, ((C 1 -C 6 )alkoxy)CO(C 1 -C 6 )alkoxy-, phenyl, benzyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-NH(C 1 -C 6 )alkyl-R 14 , —CN, —SH, —OR 11 , —CONR 5 R 6 , —(C 1 -C 6 alkyl)-CO—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl)sulfonyl, ((C 1 -C 6 )alkyl)sulfonyl(C 1 -C 6 )alkyl-, —NH—SO 2 (C 1 -C 6 )alkyl, NH 2 —SO 2 (C 1 -C 6 )alkyl-, —N(SO 2 (C 1 -C 6 )alkyl) 2 , —C(═NH)NH 2 , —NH—CO—(C 1 -C 6 )alkyl, —NH—CO—NH 2 , —NH—C(═O)—NH—(C 1 -C 6 )alkyl, —NH—C(═O)-(6- to 14-membered)aryl, —NH—C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —NH—(C 1 -C 6 )alkyl-CO—OR 7 , —NH—C(═O)—(C 1 -C 6 )alkyl-CO—OR 7 , —NH—C(═O)—CH(NH 2 )—(C 1 -C 6 )alkyl-CO—OR 7 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, -(6- to 14-membered)aryloxy, —(C 1 -C 6 )alkoxy-C(O)NR 5 R 6 , —NH—(C 1 -C 6 )alkyl-C(O)—NR 5 R 6 , —C(O)NH—(C 1 -C 6 )alkyl-COOR 7 , ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 
         R 3  is —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, or —(C 2 -C 6 )alkynyl; 
         R 4  is —OH or —(C 1 -C 5 )alkoxy; 
         R 5  and R 6  are each independently
 a) hydrogen, —OH, halo, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo); 
 b) —(C 2 -C 5 )alkenyl, —(C 2 -C 5 )alkynyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , —(C 1 -C 6 )alkoxy, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from —OH, halo, —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 1 -C 10 )alkoxy, —(C 3 -C 12 )cycloalkyl, —CHO, —C(O)OH, —C(halo) 3 , —CH(halo) 2 , CH 2 (halo), —(CH 2 ) n —O—(CH 2 ) n —CH 3 , phenyl, or CONR 5 R 6 ; 
 c) —(C 3 -C 8 )cycloalkyl, ((C 3 -C 8 )cycloalkyl)-(C 1 -C 6 )alkyl-, —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —CONH 2 , or (C 1 -C 6 )alkyl-CONH—; 
 d) ((6- to 14-membered)aryl) optionally substituted with 1, 2, or 3 independently selected R 30  groups; or 
 e) R 5  and R 6  together with the nitrogen atom to which they are attached form a (4- to 8-membered)heterocycle optionally substituted with 1, 2, or 3 independently selected R 30  groups; 
 
         R 5a  and R 6a  are each independently selected from the group consisting of:
 a) hydrogen, —OH, halo, —C(halo) 3 , —CH(halo) 2 , and —CH 2 (halo); 
 b) —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , and —(C 1 -C 6 )alkoxy, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from —OH, halo, —(C 1 -C 10 )alkyl, —(C 2 -C 12 )alkenyl, —(C 2 -C 12 )alkynyl, —(C 1 -C 10 )alkoxy, —(C 3 -C 12 )cycloalkyl, —CHO, —COOH, —C(halo) 3 , —CH(halo) 2 , CH 2 (halo), —(CH 2 ) n —O—(CH 2 ) n —CH 3 , and phenyl; 
 c) —(C 3 -C 8 )cycloalkyl, ((C 3 -C 8 )cycloalkyl)-(C 1 -C 6 )alkyl-, —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —CONH 2 , and (C 1 -C 6 )alkyl-CONH—; 
 d) -(6- to 14-membered)aryl optionally substituted with 1, 2, or 3 independently selected R 30  groups; or 
 e) R 5a  and R 6a  together with the nitrogen atom to which they are attached form a (4- to 8-membered)heterocycle optionally substituted with 1, 2, or 3 independently selected R 30  groups; 
 
         each R 7  is independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 12 )cycloalkyl, —(C 4 -C 12 )cycloalkenyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, and ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-; 
         each R 8  is methyl or ethyl; 
         each R 9  is independently phenyl, or CONR 5a R 6a ; 
         each R 11  is independently selected from —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —(C 2 -C 5 )alkenyl, —(C 2 -C 5 )alkynyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , (6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, and ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-; 
         each R 14  is independently selected from —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —C(═O)—(C 1 -C 6 )alkyl-COOR 7 , —(C 1 -C 6 )alkyl-C(═O)—(C 1 -C 6 )alkyl-COOR 7 , CONH 2 , or —(C 1 -C 6 )alkyl-CONH; 
         each R 30  is independently selected from COOR 7 , CONR 5a R 6a , —C(═O), CN, -(3- to 12-membered)heteroaryl, ((3- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, NH 2 , halo, and ((6- to 14-membered)aryl)-(C 1 -C 6 )alkoxy-; 
         m is an integer 1, 2, 3, 4, 5, or 6; 
         n is an integer 0, 1, 2, 3, 4, 5, or 6; 
         s in an integer 1, 2, 3, 4, 5, or 6; 
         provided that when R 4  is —(C 1 -C 5 )alkoxy then:
 R 2a  and R 2b  cannot be taken together to form ═O; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. A compound of  claim 1  having Formula IA′: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       3. A compound of  claim 1  having Formula IB′: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       4. A compound of claim having Formula IC′: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       5. A compound of  claim 1  having Formula ID′: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       6. A compound of  claim 1 , wherein R 2a  is hydrogen. 
     
     
       7. A compound of  claim 1 , wherein R 2a  is OH. 
     
     
       8. A compound of  claim 1 , wherein G is NR 8 . 
     
     
       9. A compound of  claim 1 , wherein G is NR 8 , and R 8  is methyl. 
     
     
       10. A compound of  claim 1 , wherein G is ═CH. 
     
     
       11. A compound of  claim 1 , wherein G is ═N—O. 
     
     
       12. A compound of  claim 1 , wherein R 10  is a -(6 to 14-membered)aryl or ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, optionally substituted with —(C 1 -C 6 )alkyl-CO—NR 5 R 6 , or NH 2 —SO 2 (C 1 -C 6 )alkyl-. 
     
     
       13. A compound of  claim 1 , wherein R 10  is optionally substituted phenyl or benzyl. 
     
     
       14. A compound of  claim 1 , wherein R 10  is piperidinyl optionally substituted with COOR 7  or NH 2 . 
     
     
       15. A compound of  claim 1 , wherein R 10  is pyrrolidinyl. 
     
     
       16. A compound of  claim 1 , wherein R 10  is -(5- to 12-membered)heteroaryl. 
     
     
       17. A compound of  claim 1 , wherein R 10  is optionally substituted pyridinyl. 
     
     
       18. A compound of  claim 1 , wherein R 10  is furanyl. 
     
     
       19. A compound of  claim 1 , wherein R 10  is —C(═O) or —C(═O)—(C 2 -C 6 )alkenyl, optionally substituted with a -(6- to 14-membered)aryl or -(5- to 12-membered)heteroaryl. 
     
     
       20. A compound of  claim 1 , wherein R 10  is —C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, optionally substituted with halo. 
     
     
       21. A compound of  claim 1 , wherein R 10  is NR 5 R 6 . 
     
     
       22. A compound of  claim 21 , wherein at least one of R 5  and R 6  is hydrogen. 
     
     
       23. A compound of  claim 21 , wherein one of R 5  and R 6  is hydrogen, and the other is —(C 1 -C 6 )alkyl-COOR 7 . 
     
     
       24. A compound of  claim 1 , wherein R 10  is CONR 5 R 6 . 
     
     
       25. A compound of  claim 24 , wherein at least one of R 5  and R 6  is -(6- to 14-membered)aryl substituted with one R 30 . 
     
     
       26. A compound of  claim 25 , wherein said R 30  is COOR 7 . 
     
     
       27. A compound of  claim 26 , wherein R 7  is hydrogen. 
     
     
       28. A compound of  claim 1 , wherein R 2a  is hydrogen, and R 2b  is —Z-G-R 10 , wherein Z is absent, G is NR 8 , R 8  is methyl or ethyl, and R 10  is ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-. 
     
     
       29. A compound of  claim 1 , wherein R 2a  is hydrogen, and R 2b  is —Z-G-R 10 , wherein Z is absent, G is NR 8  wherein R 8  is methyl or ethyl, and R 10  is —C(═O) substituted with a (6- to 14-membered)aryl. 
     
     
       30. A compound of  claim 1 , wherein R 2a  is hydrogen, and R 2b  is —Z-G-R 10 , wherein Z is absent, G is NR 8  wherein R 8  is methyl or ethyl, and R 10  is -(6- to 14-membered)aryl substituted with NH 2 —SO 2 (C 1 -C 6 )alkyl-. 
     
     
       31. A compound of  claim 1 , wherein R 2a  is hydrogen, and R 2b  is —Z-G-R 10 , wherein Z is absent, G is NR 8  wherein R 8  is methyl or ethyl, and R 10  is —C(═O)—(C 2 -C 6 )alkenyl substituted with -(5- to 12-membered)heteroaryl or -(3-to-12-membered)heterocycle. 
     
     
       32. A compound of  claim 1 , wherein R 2a  is hydrogen, and R 2b  is —Z-G-R 10 , wherein Z is absent, G is NR 8  wherein R 8  is methyl or ethyl, and R 10  is CONR 5 R 6  wherein one of R 5  or R 6  is hydrogen and the other is —(C 1 -C 6 )alkyl-COOR 7 . 
     
     
       33. A compound of  claim 1 , wherein R 2a  is hydrogen, and R 2b  is —Z-G-R 10 , wherein Z is absent, G is NR 8  wherein R 8  is methyl or ethyl, and R 10  is CONR 5 R 6  wherein one of R 5  or R 6  is hydrogen and the other is —(C 1 -C 6 )alkyl-COOR 7 . 
     
     
       34. A compound of  claim 1 , wherein R 2a  is hydrogen, and R 2b  is —Z-G-R 10 , wherein Z is absent, G is NR 8  wherein R 8  is methyl or ethyl, and R 10  is —C(═O)—(C 2 -C 6 )alkenyl substituted with -(3- to 12-membered)heterocycle. 
     
     
       35. A compound selected from the group consisting of:
 2-(((8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-ylidene)amino)oxy)acetic acid; 
 8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-one oxime; 
 8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-one-O-(2-(diethylamino)ethyl) oxime; 
 8-methoxy-3,6-dimethyl-11-propylidene-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine; 
 3-(cyclopropylmethyl)-8-methoxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-one O-methyl oxime; 
 (Z)-ethyl 2-(8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-ylidene)acetate; 
 (Z)-2-(8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-ylidene)acetic acid; 
 ethyl 2-((6S,11R)-8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)acetate; 
 2-((6S,11R)-8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)acetic acid; 
 (E)-3-(furan-3-yl)-N-((6R,11R)-8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-N-methylacrylamide; 
 8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-one oxime; 
 4-(11-(hydroxyimino)-8-methoxy-6-methyl-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocin-3(4H)-yl)-N,N-dimethyl-2,2-diphenylbutanamide; 
 (E)-3-(furan-3-yl)-N-((6R,11S)-8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-N-methylacrylamide; 
 (E)-3-(furan-3-yl)-N-((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-N-methylacrylamide; 
 (E)-N-ethyl-3-(furan-3-yl)-N-((2R,6R,11S)-8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)acrylamide; 
 4-fluoro-N′-((2S,6R)-8-methoxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-ylidene)benzohydrazide; 
 N-((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-N-methyl-2-(4-(methylsulfonyl)phenyl)acetamide; 
 4-(((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)(methyl)amino)-4-oxobutanoic acid; 
 (2R,6R,11S)-3,6-dimethyl-11-(methyl(phenethyl)amino)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol; 
 tert-butyl 4-((((2R,6S,11R)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)(methyl)amino)methyl)piperidine-1-carboxylate; 
 N-((2R,6R,11R)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-N-methylbenzamide; 
 4-(3-((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-3-methylureido)benzoic acid; 
 4-(3-((2R,6R,11R)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-3-methylureido)benzoic acid; 
 3-(((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)(methyl)carbamoyl)benzoic acid; 
 3-(((2R,6R,11R)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)(methyl)carbamoyl)benzoic acid; 
 2-(((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)(methyl)carbamoyl)benzoic acid; 
 2-(4-(((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)(methyl)amino)phenyl)ethanesulfonamide; 
 (E)-N-((2R,6R,11S)-3-(cyclopropylmethyl)-8-methoxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-3-(furan-3-yl)-N-methylacrylamide; 
 4-(((2R,6R,11R)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)(methyl)carbamoyl)benzoic acid; 
 3-(3-((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-3-methylureido)propanoic acid; 
 2-(((2R,6R,11S)-3-(cyclopropylmethyl)-8-methoxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)(methyl)amino)acetic acid; 
 2-(3-((2R,6S,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-3-methylureido)-4-methylpentanoic acid; 
 (E)-N-((2R,6R,11S)-3-(cyclopropylmethyl)-8-hydroxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-3-(furan-3-yl)-N-methylacrylamide; 
 3-(4-cyanophenyl)-1-((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-1-methylurea; 
 3-(4-cyanophenyl)-1-((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-1-methylurea; and 
 the pharmaceutically acceptable salts thereof. 
 
     
     
       36. A compound selected from the group consisting of:
 3-(4-cyanophenyl)-1-((6R,11R)-3-(cyclopropylmethyl)-8-hydroxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-1-methylurea; 
 3-(4-cyanophenyl)-1-((6R,11S)-3-(cyclopropylmethyl)-8-hydroxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-1-methylurea; 
 4-(3-((6R,11S)-3-(cyclopropylmethyl)-8-methoxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-3-methylureido)benzamide; 
 (E)-N-((6R,11R)-3-(cyclopropylmethyl)-8-hydroxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-3-(furan-3-yl)-N-methylacrylamide; 
 4-((2R,6R,11S)-11-(3-(4-cyanophenyl)-1-methylureido)-8-hydroxy-6-methyl-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocin-3(4H)-yl)-N,N-dimethyl-2,2-diphenylbutanamide; 
 (E)-N-((2R,6R,11S)-3-(cyclopropylmethyl)-8-methoxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-3-(furan-3-yl)-N-methylacrylamide; 
 (Z)—N-((2R,6R,11S)-3-(cyclopropylmethyl)-8-methoxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-3-(furan-3-yl)-N-methylacrylamide; 
 3-(4-cyanophenyl)-1-((2R,6R,11S)-8-hydroxy-6-methyl-3-phenethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-1-methylurea; 
 3-(4-cyanophenyl)-1-((6R,11R)-3-(cyclobutylmethyl)-8-hydroxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-1-methylurea; 
 3-(4-cyanophenyl)-1-((6R,11R)-3-(2,3-difluorobenzyl)-8-hydroxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-1-methylurea; 
 3-(4-cyanophenyl)-1-((2R,6R,11S)-3-(furan-3-ylmethyl)-8-hydroxy-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-1-methylurea; and 
 the pharmaceutically acceptable salts thereof. 
 
     
     
       37. A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically salt thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
       38. A method for modulating opioid receptor function in a cell, comprising contacting a cell capable of expressing an opioid receptor with an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the opioid receptor is an μ-opioid receptor, κ-opioid receptor, or ORL-1 receptor. 
     
     
       39. The method of  claim 38 , wherein the compound modulates μ-opioid receptor function. 
     
     
       40. The method of  claim 38 , wherein the compound acts as an agonist at the μ-opioid receptor. 
     
     
       41. The method of  claim 38 , wherein the compound acts as an antagonist at the μ-opioid receptor. 
     
     
       42. The method of  claim 38 , wherein the compound acts as an agonist at the κ-opioid receptor. 
     
     
       43. A method of treating a pain or constipation in a mammal, comprising administering to such mammal in need thereof an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof.